Immunomodulatory Therapy for Neuropathic Pain

神经性疼痛的免疫调节疗法

• 批准号: 10490450
• 负责人: RIDONG CHEN
• 金额: $ 92.25万
• 依托单位: APT THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10490450
• 关键词: Address; Affect; Affinity; Aldesleukin; American; Analgesics; Animal Model; Anti-Inflammatory Agents; Anticonvulsants; Antidepressive Agents; Attenuated; Autoimmune; Autoimmune Diseases; Benefits and Risks; Binding; Binding Sites; Blood Glucose; Blood Vessels; CD8-Positive T-Lymphocytes; Cell Count; Cell physiology; Cells; Cessation of life; Chimeric Proteins; Clinical Research; Cyclic GMP; Data; Development; Diabetic Neuropathies; Disease; Dose; Escherichia coli; FOXP3 gene; Functional disorder; GTP-Binding Proteins; Generations; Goals; Half-Life; Homeostasis; Human; IL2 gene; IL2RA gene; Immune; In Vitro; Infection; Injections; Insulin-Dependent Diabetes Mellitus; Interferons; Interleukin-2; Kidney; Lesion; Lidocaine; Maintenance; Malignant Neoplasms; Mammalian Cell; Mechanics; Mediating; Memory; Modeling; Mononeuropathies; Mutation; NK Cell Activation; Natural Killer Cells; Nervous system structure; Neurons; Norepinephrine; Opioid; Pain; Pathogenicity; Pathway interactions; Patients; Peripheral nerve injury; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Plasma; Polyneuropathy; Postherpetic neuralgia; Prevention strategy; Principal Investigator; Quality of life; Rattus; Reaction; Recombinant Proteins; Regulatory T-Lymphocyte; Renal carcinoma; Reporting; Safety; Self Tolerance; Sensory Ganglia; Serotonin; Serum Albumin; Severities; Site; Streptozocin; Symptoms; Syndrome; Th1 Cells; Therapeutic; Therapeutic Index; Thymus Gland; Toxic effect; Trigeminal Neuralgia; United States; Variant; Work; addiction; allodynia; analog; base; chronic constriction injury; chronic pain; cytokine; design; diabetic; diabetic rat; drug candidate; drug development; duloxetine; effector T cell; eosinophil; experience; functional status; gabapentin; immunomodulatory therapies; improved; inhibitor; innovation; macrophage; manufacturing process; mechanical allodynia; melanoma; molecular size; neuroinflammation; neurotransmission; non-opioid analgesic; novel; novel strategies; novel therapeutics; opioid epidemic; opioid overdose; pain relief; painful neuropathy; phase 1 study; post stroke pain; pregabalin; prevent; programs; receptor; response; restoration; reuptake; sciatic nerve; side effect; somatosensory; symptom management; symptom treatment; type I diabetic

Principal Investigator/Program Director (Last, First, Middle: Ridong Chen Project Summary More than 25 million Americans suffer from chronic pain. Due to the lack of other treatments, there has been an overreliance on opioids, contributing to an alarming epidemic of opioid overdose addictions and deaths. Neu- ropathic pain is difficult to treat, with only 30-40% of patients achieving meaningful (>40-50%) pain relief. Current therapies (e.g., duloxeline and gabapentin) mainly address symptoms by focusing on blocking neurotransmis- sion in the pain pathway with limited efficacy, severe side effects, and narrow therapeutic indices. Hence, novel non-opioid therapies are urgently needed to safely manage symptoms and also target the underlying pathophys- iological mechanisms that will improve the functional status and quality of life of affected patients. It has been recently shown that CD4+ Th1 is a major player for neuropathic pain development. Interleukin-2 (IL-2) is the key cytokine for the generation, survival, and function of regulatory T cells by direct binding to its high affinity receptor. Treatment with low-dose rIL-2 increased anti-inflammatory regulatory T cells and M2 type macrophages and inhibited pathogenic interferon- secreting T helper type 1 cells. This rIL-2 treatment was efficacious in human clinical studies for autoimmune diseases without complications or infections. Hence, resto- ration or enhancement of regulatory T cells with low-dose IL2 may offer a novel strategy for prevention and treatment of neuropathic pain. However, several drawbacks exist for current low-dose rIL2 therapy, including a short half-life, propensity for in vitro aggregation causing adverse local reaction at injection sites, and a potential narrow therapeutic window. We have designed proprietary IL2-based variants that will enable selective stimu- lation of Tregs with an extended half-life and a broad therapeutic window. In the Phase I study, we successfully identified the variant, designated APT603, which selectively stimulates regulatory T cells and provides robust analgesic efficacy in the chronic constriction injury model of mononeuropathy in rats with an excellent safety profile. With an experienced drug development team, we propose to determine dose responses in two well es- tablished models of neuropathic pain with distinct pathophysiology and to conduct critical activities necessary to enable IND filing for APT603.  Specific Aim 1: Determine the therapeutic index of APT603 for abrogating neuropathic pain in STE- induced (T1D) diabetic rats and in a rat model of sciatic nerve chronic constriction injury (CCI).  Specific Aim 2: Manufacture cGMP (Current Good Manufacturing Practice) grade APT603.  Specific Aim 3: Evaluate the nonclinical safety of APT603. The long-term goal is to develop the drug candidate as a safe and disease-modifying analgesic therapy. Weekly or bi-weekly dosing will provide sustained neuropathic pain relief for patients without inducing significant side effects, tolerance, or addiction.

首席研究员/项目总监(倒数第一中：陈日东